2-chloro-6-hydroxynicotinic acid

ABSTRACT

2-Chloro-6-hydroxynicotinic acid, useful as an agent for inhibiting the synthesis of lipids and, consequently, reducing the weight of accumulated fat in warm-blooded animals, is described.

United States Patent Beaman et al. [451 Aug. 8, 1972 [54] 2-CHLORO-6-HYDROXYNICOTINIC [56] References Cited ACID OTHER PUBLICATIONS [72] Inventors: Alden Gamaliel Beaman, North Caldwell; 0. Neal Miller, Momdair, Johnson et al., Chem. Abstracts, Vol. 71, No. 15, 69, both fN -'l3l(b), Oct. I3, 1969 [73] Assignee: Hoffmann-La Roche Inc., Nutley, primary E L Roman Atl0rneySamuel L. Welt, Jon S. Saxe, Bernard S. [22] Filed; N0 23 970 Leon, William G. lsgro and Margaret C. Bogosian [21] Appl. No.: 92,295 57 ABSTRACT 2-Chloro-6-hydroxynicotinic acid, useful as an agent [52] Cl "260/2955 260/293-69 424/266 for inhibiting the synthesis of lipids and, consequently, 424/267 reducing the weight of accumulated fat in warm- [51] Int. Cl. ..C07d 31/36 blooded animals, is described [58] Field of Search ..260/295.5, 293.69

2 Claims, No Drawings 1 2-CHLORO-6-HYDROXYNICOTINIC ACID BRIEF SUMMARY OF THE INVENTION The invention relates to 2-chloro-6-hydroxynicotinic acid and salts thereof formed with pharmaceutically acceptable bases.

DETAILED DESCRIPTION OF THE INVENTION The invention relates to 2-chloro-6-hydroxynicotinic acid and salts thereof formed with pharmaceutically acceptable bases.

The compound of the invention can exist and be used either in its free acid form or as a salt formed with pharmaceutically acceptable bases. Such salts can be prepared, for example, by reaction with a base having a non-toxic, pharmaceutically acceptable cation. Thus, any base which will fonn a salt with a carboxylic acid and will not be toxic or have adverse pharmacological effects can be utilized. Exemplary of such bases are the alkali metal and alkaline earth metal hydroxides, carbonates and the like, for instance, sodium hydroxide, potassium hydroxide, calcium hydroxide and calcium carbonate, ammonia, primary, secondary and tertiary amines, such as mono-, dior trialkylamines, for instance, methylamine, dimethylarnine and trimethylamine, and nitrogen containing heterocyclic amines, for instance, piperidine and the like.

The compound of the invention lowers the lipids level in warm-blooded animals, and thus is useful in reducing the weight of accumulated fat in warmblooded animals.

For such use, the presently disclosed compound is formulated, using conventional inert pharmaceutical adjuvant materials, into dosage forms which are suitable for oral or parenteral administration. Such dosage forms include tablets, suspensions, solutions and the like. Furthermore, the compound of the invention can be incorporated into, and administered in the form of, suitable hard or soft capsules. The identity of the inert adjuvant materials which are used in formulating the present compound into oral and parenteral dosage forms will be immediately apparent to persons skilled in the art. These adjuvant materials, either inorganic or organic in nature, include, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, and the like Moreover, preservatives, stabilizers, wetting agents, emulsifying agents, salts for altering osmotic pressure, buffers, and the like, can be incorporated, if desired, into such formulations.

The quantity of active medicament which is present in any of the above-described dosage forms is variable. It is preferred, however, to provide capsules or tablets containing from about 100 mg. to about 1,000 mg. of 2- chloro-6-hydroxynicotinic acid or an equivalent amount of a pharmaceutically acceptable salt thereof formed with a base.

The frequency with which any such dosage form will be administered to a warm-blooded animal will vary, depending upon the quantity of active medicament present therein and the needs and requirements of the warm-blooded animal, as diagnosed by the prescriber.

Under ordinary circumstances, however, up to about 6 500 mg. of 2-chloro-6-hydroxynicotinic acid can be administered daily irr several dosages. It is to be understood, however, that the dosages set forth therein are exemplary only and that they do not, to any extent, limit the scope or practice of this invention.

The 2-chloro-6-hydroxynicotinic acid of the invention can be prepared by treating 2,6-dichloronicotinic acid with a base, for example, an alkali metal hydroxide, such as sodium hydroxide, potassium hydroxide and the like, preferably at the reflux temperature of the reaction mixture, subsequently acidifying the resulting mixture with an acid, for example, a hydrohalic acid such as hydrochloric acid, and thereafter recovering the desired end product.

The following examples further illustrate the invention. All temperatures are in degrees Centigrade, unless otherwise mentioned.

EXAMPLE 1 Preparation of 2-chloro-6-hydroxynicotinic acid A mixture of 6.00 g. of 2,6-dichloronicotinic acid and 78 ml. of 2N NaOH solution was refluxed for 2 hours, cooled, and acidified with 17 rrrl. of 10 N l-ICl. The mixture was cooled 30 minutes in an ice bath, and the solid was filtered and washed with water. The solid was slurried in 25 ml. of warm ethanol, filtered and washed with warm ethanol. The ethanol insoluble solid, mp. 296298 dec. was recrystallized from 1,500 ml. of 1:2 vol:vol. ethanolzwater to give 2-chloro-6-hydroxynicotinic acid, having a melting point of 300-302 dec.

1. 2-Chloro-6-hydroxy nicotinic acid, lactose, corn starch, and prehydrolyzed corn starch are blended in a suitable mixer.

2. The mixture is granulated to a heavy paste with water and the moist mass is passed through a No. 12 screen, and then dried overnight at l 10 F.

3. The dried granules are passed through a No. 16

screen and transferred to a suitable mixer. The calcium stearate is added and mixed until uniform.

4. The mixture is compressed at a tablet weight of 410 mg. using tablet punches having a diameter of approximately three-eighths inch. (Tablets may be either flat or biconvex and may be scored if desired.)

EXAMPLE 3 Tablet Formulation Per Tablet 2-Chloro-6-hydroxynicotinic acid 250.0 mg. 5 Lactose 200.0 mg. Corn Starch 100.0 mg. Pregelatinized Corn Starch 25.0 mg. Calcium Stearate 10.0 mg. Total Weight: 585.0 mg.

Procedure:

1. 2-Chloro-6-hydroxynicotinic acid, lactose, corn starch and pregelatinized corn starch are mixed in a suitable mixer.

2. The mix is passed through a Fitzpatrick Comminuting Machine fittedwith No. 1A screen, with knives forward.

3. The mixture is returned to the mixer and moistened with water to a thick paste. The moist mass is passed through a No. 12 screen, and the moist granules are dried on paper-lined trays at 1 F.

4. The dried granules are returned to the mixer, and

the calcium stearate is added and mixed well.

5. The granules are compressed at a tablet weight of 585 mg. using standard concave punches having a diameter of approximately 12.7 mm. (one-half inch).

EXAMPLE 4 Capsule Formulation Per Capsule 2-Chloro-6-hydroxynicotinic acid 250.0 mg. Lactose 60.0 mg. Com Starch 35.0 mg. Talc 5.0 mg. Total Weight: 350.0 mg.

Procedure:

1. 2-Chloro-6-hydroxynicotinic acid, lactose and corn starch are mixed in a suitable mixer.

2. The mixture is passed through a Fitzpatrick Comminuting Machine using a No. 1A screen, with knives forward.

3. The mixture is returned to the mixer and the talc is added. This mixture is then blended well and filled into No. 2 two-piece, hard shell gelatin capsules on a capsulating machine.

We claim: V

1. A compound selected from the group consisting of 2-chloro-6-hydroxynicotinic acid and its salts formed with pharrnaceutically acceptable bases.

2. A compound in accordance with claim 1, 2- chloro-6-hydroxynic0tinic acid. 

2. A compound in accordance with claim 1, 2-chloro-6-hydroxynicotinic acid. 